Chemotherapy and radiation therapy are two common methods to treat cancer. Both treatments can induce single-stranded and/or double-stranded DNA breakage to produce cytotoxicity, then the targeted tumor cells will die due to chromosomal damage. An important result in response to DNA damage signal is that the signal of the cell cycle in regulation site is activated, the purpose of which is to protect cells from mitosis in the case of DNA damage thereby preventing cell damage. In most cases, the tumor cells exhibit the defects of regulation signal in the cell cycle and have high proliferation rate. So it can be predicted that the tumor cells have specific DNA repair mechanisms, which can respond quickly to repair chromosome damage relevant to proliferation regulation, thereby saving them from cytotoxic effects of some treatment and keep alive.
In the clinical application, the effective concentration of the chemotherapeutical drug or therapeutic radiation intensity can fight these DNA repair mechanism to ensure the killing effect on the target tumor cells. However, the tumor cells can develop tolerance for treatment by enhancing its DNA damage repair mechanisms, and survive from the lethal DNA damage. In order to overcome the tolerance, it is usually necessary to increase the dosage of the therapeutic drug or radiation intensity. This approach will produce adverse effects on the normal tissue nearby the lesions, and then make the treatment course complicated by severe adverse reactions, thereby increasing the risk of treatment. At the same time, the ever-increasing tolerance will reduce the therapeutic effect, so it can be concluded that the cytotoxicity of the DNA damage agents can be improved in the way of tumor cell-specificity by controlling the repair mechanism promoted by the signal of DNA damage.
PARPs (Poly (ADP-ribose) polymerases), characterized by poly ADP-ribosylation activity, are constituted by the superfamily of 18 nucleus enzymes and cytoplasmic enzymes. Such poly ADP-ribosylation effect can adjust the activity of the targeted protein and the interaction between proteins, and regulate other many fundamental biological processes, including DNA repair and cell death. In addition, genomic stability is also associated with the poly ADP-ribosylation (see D'Amours et al. Biochem. J, 1999, 342, 249).
The activity of PARP-1 accounts for about 80% of the total cellular PARP activity. PARP-1, together with PARP-2, which is most similar to PARP-1, are the members having the DNA damage repair capacity in the PARP family. As a sensor and a signaling protein of DNA damage, PARP-1 can detect the DNA damage sites quickly and bond to them directly, and then induce the aggregation of various proteins required for DNA repair, thereby enabling the DNA damage to be repaired. When the cells lack PARP-1, PARP-2 can realize the repair of the DNA damage instead of PARP-1.
Studies have shown that, compared with normal cells, the expression of PARPs protein in solid tumors is generally enhanced. In addition, the tumors (such as breast cancer and ovarian cancer), whose DNA repair related gene is missing (such as BRCA-1 or BRCA-2), show extreme sensitivity to PARP-1 inhibitors. This suggests the potential uses of PARP inhibitors as a single agent in the treatment of a tumor, which can be called triple negative breast cancer (see Plummer, E. R. Curr. Opin. Pharmacol. 2006, 6, 364; Ratnam, et al; Clin. Cancer Res. 2007, 13, 1383). At the same time, because DNA damage repair mechanism is the main mechanism of tumor cells response to the tolerance produced by chemotherapeutic drugs and ionizing radiation treatment, PARP-1 is considered to be an effective target to explore the new methods of cancer therapy.
PARP inhibitors were initially developed and designed using nicotinamide of NAD+, which can be used as PARP catalytic substrate, as a template to develop its analogs. As competitive inhibitors of NAD+, these inhibitors compete with NAD+ for PARP catalytic sites, thereby preventing the synthesis of the poly (ADP-ribose) chain. PARP without poly (ADP-ribosylation) modification cannot be dissociated from the DNA damage sites, which will lead other proteins involved in the repair into the damage site, thereby preventing performance of the repair process. Therefore, in the effect of the cytotoxic drugs or radiation, PARP inhibitor will eventually kill tumor cells with DNA damage.
In addition, the NAD+, which is consumed as the PARP catalytic substrate, is the essential factor in the ATP synthesis process of the cells. Under the high level of PARP activity, intracellular NAD+ levels will significantly decrease, thereby affecting the intracellular ATP level. Due to lack of intracellular ATP content, the cells cannot achieve programmed ATP-dependent cell death process, and can only turn to necrosis, a special apoptosis process. During the necrosis, a lot of inflammatory cytokines will be released, thereby producing toxic effects on other organs and tissues (Horvath E M et al. Drug News Perspect, 2007, 20, 171-181). Therefore, PARP inhibitors can also be used for the treatment of a variety of diseases related to this mechanism, including neurodegenerative diseases (such as Alzheimer's disease, Huntington's disease, Parkinson's disease), diabetes, concurrent diseases in the ischemia or ischemia-reperfusion process, such as myocardial infarction and acute renal failure, circulatory system diseases, such as septic shock and inflammatory diseases, such as chronic rheumatism, etc (see Tentori L, et al. Pharmacol. Res., 2002, 45, 73-85; Horvath E M et al. Drug News Perspect., 2007, 20, 171; Faro R, et al. Ann. Thorac. Surg., 2002, 73, 575; Kumaran D, et al. Brain Res., 2008, 192, 178).
Currently, a series of patent application have been disclosed on phthalazinone ketone PARP inhibitor, including WO2002036576, WO2004080976 and WO2006021801.
Although there are a series of PARP inhibitors for tumor treatment that have been disclosed, there remains a need to develop new compounds with better efficacy and pharmacokinetics results. After continuous efforts, the present invention designs a series of compounds of formula (I), and finds that the compounds having such structure exhibit an excellent effect and function.